Differential effects of nifedipine, verapamil, and diltiazem on noradrenaline-induced contractions, adrenergic transmitter release, and alpha-adrenoceptor binding in the female rabbit urethra

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Abstract
In order to study differences in action between “Ca2+-entry blockers” on smooth muscle and peripheral nerves, the effects of nifedipine, verapamil, and diltiazem on noradrenaline (NA)-induced contractions and electrically evoked release of 3H-NA were investigated in the female rabbit urethra. In addition, possible influences of Ca2+-entry blockers on alpha-adrenoceptors were studied with radioligand binding technique. Exposure to Ca2+-free medium completely abolished the contractile response to 1 μM NA in the rabbit urethra, indicating that the contraction was entirely dependent on influx of extracellular Ca2+. The Ca2+-entry blockers inhibited the NA-induced contractions in the following order of potency: nifedipine>verapamil≈diltiazem. In contrast to nifedipine and diltiazem, which produced a maximum inhibition of between 50 and 60%, verapamil was able to abolish the contractile responses to NA. The electrically evoked efflux of 3H-NA was decreased by diltiazem and increased by verapamil, whereas nifedipine failed to alter the 3H-NA efflux. Only verapamil was effective in inhibiting specific 3H-DHE binding to a crude membrane preparation of the rabbit bladder base and urethra, and the inhibition appeared to be of the competitive type. It is suggested that the effects of verapamil on electrically evoked efflux of 3H-NA and on NA-induced contractions can be partly explained by blockade of pre- and post-junctional alpha-adrenoceptors. The failure of nifedipine and diltiazem to abolish the NA-induced contraction might indicate the existence of different Ca2+-entry pathways in urethral smooth muscle.